U.S. patent number 8,748,494 [Application Number 12/797,059] was granted by the patent office on 2014-06-10 for method for improving the therapeutic efficacy of curcuminoids and their analogs.
This patent grant is currently assigned to ASAC Compnia de Biotecnologia e Investigacion, S.A.. The grantee listed for this patent is August Bernd, Joaquin Diaz Alperi, Ana Adela Ramirez Bosca. Invention is credited to August Bernd, Joaquin Diaz Alperi, Ana Adela Ramirez Bosca.
United States Patent |
8,748,494 |
Diaz Alperi , et
al. |
June 10, 2014 |
Method for improving the therapeutic efficacy of curcuminoids and
their analogs
Abstract
The invention relates to a method for increasing the therapeutic
efficacy of curcuminoids and analogs. More specifically, the
invention relates to a method for increasing the therapeutic
efficacy of systemically administered formulations that contain
curcuminoids and the equivalent therapeutics thereof. The method is
characterized in that together with the administration of the
formulation the patient is irradiated with visible, and optionally
ultraviolet, radiation during a treatment. The invention also
relates to phototherapy devices that emit visible radiation over a
surface area greater than 0.2 m.sup.2 with an irradiance of more
than 2 mW/cm.sup.2, the devices being suitable for use in the
treatment of proliferative diseases, particularly
moderate-to-severe psoriasis or tumor processes.
Inventors: |
Diaz Alperi; Joaquin (Alicante,
ES), Ramirez Bosca; Ana Adela (Alicante,
ES), Bernd; August (Bingen, DE) |
Applicant: |
Name |
City |
State |
Country |
Type |
Diaz Alperi; Joaquin
Ramirez Bosca; Ana Adela
Bernd; August |
Alicante
Alicante
Bingen |
N/A
N/A
N/A |
ES
ES
DE |
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Assignee: |
ASAC Compnia de Biotecnologia e
Investigacion, S.A. (Alicante, ES)
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Family
ID: |
40800743 |
Appl.
No.: |
12/797,059 |
Filed: |
June 9, 2010 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20100298444 A1 |
Nov 25, 2010 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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PCT/ES2008/000787 |
Dec 19, 2008 |
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PCT/ES2007/000753 |
Dec 19, 2007 |
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Foreign Application Priority Data
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Feb 22, 2008 [EP] |
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08003253 |
Oct 31, 2008 [EP] |
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08019146 |
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Current U.S.
Class: |
514/679 |
Current CPC
Class: |
A61N
5/062 (20130101); A61N 5/06 (20130101); A61K
31/122 (20130101); A61P 35/00 (20180101); A61K
36/9066 (20130101); A61P 17/06 (20180101) |
Current International
Class: |
A01N
35/00 (20060101); A61K 31/12 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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1133992 |
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Sep 2001 |
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EP |
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WO03/039452 |
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May 2003 |
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WO |
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Other References
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cultured cells. J. Photochem Photobiol.: B. Biol. 54 (2000): 72-80.
cited by examiner .
Barzegari et al. "A comparison of three times vs five times weekly
narrowband ultraviolet B therapy for the treatment of chronic
plaque psoriasis". Photodermatol. Photoimmunol. Photomed. (Feb.
2010), 26(1):10-15. (Abstract). cited by applicant .
Hasegawa et al. "Efficacy of 308-nm excimer light for Japanese
patients with psoriasis". J. Dermatol. (Nov. 2009), 36
(11):579-582. (Abstract). cited by applicant .
Seckin et al. "Topical 8-methoxypsoralen increases the efficacy of
narrowband ultraviolet B in psoriasis". PPhotodermatol.
Photoimmunol. Photomed. (Oct. 2009), 25(5):237-241. (Abstract).
cited by applicant .
Kwon et al. "A retrospective review of 20% vs 10% incremental
narrowband UVB regimens to treat psoriasis in skin phototypes III-V
Koreans". Photodermatol. Photoimmunol. Photomed. (Jun. 2009),
25(3):124-7. (Abstract). cited by applicant .
Koek et al. "Home versus outpatient ultraviolet B phototherapy for
mild to severe psoriasis: pragmatic multicentre randomized
controlled non-inferiority trial (PLUTO study)". BMJ (May 2009),
338:b1542. (Abstract). cited by applicant .
Kircik et al. "Treatment of moderate to severe plaque psoriasis
with concomitant efalizumab and narrow-band ultraviolet B
phototherapy". J. Drugs Dermatol. (Oct. 2008), 7(10):947-952.
(Abstract). cited by applicant .
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Investigation of the photobiological activity of curcumin using
bacterial indicator systems". J. Pharm. Sci. (May 1987),
76(5):371-3. (Abstract). cited by applicant .
Shishodia et al. "Curcumin: getting back to the roots". Ann N Y
Acad Sci (Nov. 2005), 1056:206-17. (Abstract). cited by applicant
.
Kleinpenning Mm et al. "Narrowband ultraviolet B therapy in
psoriasis: randomized double-blind comparison of high-dose and
low-dose irradiation regimens". Br J Dermatol. Dec. 2009; 161(6):
1351-6. Epub Apr. 10, 2009. cited by applicant .
Cui BN. et al., "Clinical efficacy of narrow band ultraviolet bin
combined with yuyin recipe in treating psoriasis vulgaris".
Zhongguo Xi Yi Jie He Za Zhi (2008), 28(4):355-7 (abstract). cited
by applicant .
Valkova S. "UVB phototherapeutic modalities. Comparison of two
treatments for chronic plaque psoriasis." Acta Dermatovenerol Alp
Panonica Adriat (2007), 16(1):26-30 (abstract). cited by applicant
.
Sivanesan et al. "Randomized, double-blind, placebo-controlled
evaluation of the efficacy of oral psoralen plus ultraviolet A for
the treatment of plaque-type psoriasis using the Psoriasis Area
Severity Index score (improvement of 75% or greater) at 12 weeks".
J Am Acad Dermatol (Nov. 2009), 61:793-798. cited by applicant
.
Kurd et al. "Oral curcumin in the treatment of moderate to severe
psoriasis vulgaris: A prospective clinical trial.". J Am Acad
Dermatol. (Apr. 2008), 58(4):625-31. Epub Feb. 4, 2008. cited by
applicant .
Toennesen et al. "Studies on curcumin and Curcuminoids". Z Lebensm
Unters Forsch (1986),183:116-122. cited by applicant .
Casacci et al. "Comparison between 308 nm monochromatic excimer
light and narrowband UVB phototherapy (311-313 nm) in the treatment
of vitiligo a multicentre controlled study." JEADV (2007), vol.
21:956-963. cited by applicant .
Dujic et al. "Low concentrations of Curcumin Induce Growth Arrest
and Apoptosis in Skin Karatinocytes only in combination with UVA or
visible light . . . "Journal of Investigate Dermatology (2007)
127:1992-2000. cited by applicant .
Garcea, et al. "Detection of curcumin and its metabolites in
hepatic tissue and portal blood of patients following oral
administration" Br J Cancer. (Mar. 8, 2004), 90(5):1011-15. cited
by applicant .
Anand et al. "Biological activities of curcumin and its analogues
(Congeners) made by man and Mother Nature." Biochem Pharmacol.
(Dec. 1, 2008), 76(11):1590-611. Epub Aug. 19, 2008. (Abstract).
cited by applicant .
Bissonnette et al. "Systemic photodynamic therapy with
aminolevulinic acid induces apoptosis in lesional T lymphocytes of
psoriatic plaques". J Invest Dermatol (2002), 119:77-83. cited by
applicant .
Shehzad et al."Efficacy of concomitant use of PUVA and Methotrexate
in diseases clearance time in plaque type psoriases". J Pak Med.
Assoc. (2004), 54(9):453-5. (Abstract). cited by applicant .
Dalton et al., entitled "Clinical Pharmcokinetics of
5-Aminolevulinic Acid in Healthy Volunteers and Patients at High
Rish of Recurrent Bladder Cancer" in J. Pharm. Exp. Therap. (2002),
301(2), 507-512. cited by applicant.
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Primary Examiner: Pagonakis; Anna
Attorney, Agent or Firm: Matos; Rick Innovar, L.L.C.
Parent Case Text
CROSS-REFERENCE TO EARLIER FILED APPLICATIONS
The present application is a continuation-in-part of and claims the
benefit of PCT International Application No. PCT/ES08/000,787 filed
Dec. 19, 2008, which claims the benefit of PCT/ES07/000,753 filed
Dec. 21, 2007, and European Applications No. EP08003253 filed Feb.
22, 2008 and No. EP08019146 filed Oct. 31, 2008, the entire
disclosures of which are hereby incorporated by reference.
Claims
The invention claimed is:
1. A method of treating psoriasis comprising: a) orally
administering to a subject, having an affected area with psoriasis,
an effective amount of curcuminoid, wherein the curcuminoid is
curcumin; b) exposing 0.2 m.sup.2 or greater or 40 cm.sup.2 or
greater of skin of the subject to device-generated radiation having
an irradiance of 2 mW/cm.sup.2 or higher to achieve a unit
radiation dose of 1-36 J/cm.sup.2, wherein the radiation comprises
visible light radiation and optionally further comprises
ultraviolet light radiation; and c) repeating steps a) and b) until
a cumulative radiation dose of 150 to 600 J/cm.sup.2 is
achieved.
2. A method of treating psoriasis comprising: a) orally
administering to a subject, having an affected area with psoriasis,
an effective amount of curcuminoid per day, wherein the curcuminoid
is curcumin; b) exposing at least the affected area to
device-generated radiation having an irradiance of 2 mW/cm.sup.2 or
higher to achieve a radiation unit dose of 1-18 J/cm.sup.2 per
exposure or per day, wherein the radiation comprises visible light
radiation and optionally further comprises ultraviolet light
radiation; and c) repeating steps a) and b) until a cumulative
radiation dose of 150-580 J/cm.sup.2 is achieved.
3. A method of improving the therapeutic efficacy of curuminoids in
the treatment of psoriasis, the method comprising: a) orally
administering to a subject, having an affected area with psoriasis,
an effective amount of curcuminoid per day, wherein the curcuminoid
is curcumin; b) exposing 0.2 m.sup.2 or greater of skin of the
subject to device-generated visible light radiation having an
irradiance of 2 mW/cm.sup.2 or higher for a period of 5 minutes or
greater at an irradiation distance of 2 to 20 inches to achieve a
radiation unit dose of 1-36 J/cm.sup.2, the exposing being
performed one to four times or two to three times per week; and c)
repeating steps a) and b) according to a dosing regimen until a
cumulative radiation dose of 150-600 J/cm.sup.2 is achieved.
4. The method of claim 1 comprising: a) orally administering to a
subject, having an affected area with psoriasis, an effective
amount of curcuminoid per day, wherein the curcuminoid is curcumin;
b) exposing 0.2 m.sup.2 or greater of skin of the subject to
device-generated visible light radiation having an irradiance of 2
mW/cm.sup.2 or higher and a maximum wavelength in the range of 400
to 550 nm and, optionally to device-generated ultraviolet light
radiation having an irradiance of 2 mW/cm.sup.2 or higher and a
maximum wavelength in the range of 315 to 400 nm, for a period of 5
minutes or higher at an irradiation distance of 2-20 inches to
achieve a radiation unit dose of 1-36 J/cm.sup.2, the exposing
being performed on a 2 to 4 times per week basis; and c) repeating
steps a) and b) according to a dosing regimen until a cumulative
radiation dose of 150-600 J/cm.sup.2 is achieved during a period of
two weeks or more.
5. The method according to claim 3, wherein the device-generated
visible light radiation is generated by means for emitting visible
light radiation having a maximum wavelength in the range of in the
range of 400-550 nm on a surface area greater than 0.20 m.sup.2
with an irradiance greater than 2 mW/cm.sup.2.
6. The method according to claim 2, wherein the device-generated
radiation comprises visible light radiation and ultraviolet light
radiation.
7. The method according to claims 6, wherein the step of exposing
comprises exposing 0.2 m.sup.2 or greater of skin of the subject to
device-generated visible light radiation having an irradiance of 2
mW/cm.sup.2 or higher and device-generated ultraviolet light
radiation having an irradiance of 2 mW/cm.sup.2 or higher for a
period of 5 minutes or higher.
8. The method according to claim 1, wherein the device-generated
radiation has an emission maximum at about 420 nm.
9. The method according to claim 2 comprising exposing greater than
10% of the body surface area of the skin of the subject.
10. The method according to claim 2, wherein the psoriasis is
moderate, moderate to severe or severe and the subject has a
Psoriasis Area Severity Index (PASI) in the range of 10 to 20.
11. The method according to claim 2, wherein the cumulative amount
of curcuminoid administered ranges from 1400 mg to 140 g; and/or
the cumulative radiation dose of device-generated radiation ranges
from 150-300 J/cm.sup.2.
12. The method according to claim 1, wherein the dose of
Curcuminoid is 1-40 mg/kg/day.
13. The method according to claim 1, 2 or 3, wherein the
Curcuminoid is present in pure form or in the form of Curcuma longa
extract.
14. The method of claim 2, wherein the psoriasis is moderate to
severe psoriasis, and the method comprises: a) orally administering
to a subject, having a PASI ranging from 10-20, a total of 70 to 80
mg of curcuminoid on a per day basis for 3 to 8 weeks; and b)
exposing at least 0.2 m.sup.2 of skin, comprising psoriatic skin,
of the subject to 2.5 to 16 J/cm.sup.2 unit doses of
device-generated radiation on a twice weekly basis for 3 to 8
weeks, thereby providing a PASI reduction of at least 80%.
15. The method of claim 14, wherein: a) the total daily dose of
curcuminoid is divided into 2 or 3 doses; b) the unit dose of
radiation is escalated from 2.5 to 16 J/cm.sup.2 in escalation
increments of 0.5 to 1 J/cm.sup.2; c) the unit dose of radiation is
maintained at a level dose; d) the device-generated radiation has
an irradiance of 2-300 mW/cm.sup.2 to achieve a radiation unit dose
of 1 to 18 J/cm.sup.2 per 0.2 m.sup.2 of affected area in a
subject, wherein unit doses are administered on a 1 to 4 times per
week basis, for 2 to 10 weeks to provide a cumulative radiation
dose ranging from 150 to 350 J/cm.sup.2; and/or e) the cumulative
radiation dose ranges from 150 to 250, 150-200 or 170-180
J/cm.sup.2.
16. The method of claim 2, wherein the psoriasis is moderate to
severe psoriasis, and the method comprises: a) orally administering
to a subject, having a PASI ranging from 10-20, a total of 70 to 80
mg of curcuminoid on a per day basis for 3 to 8 weeks; and b)
exposing the entire naked body of a psoriatic subject to a unit
dose of about 18 J/cm.sup.2 of visible light on a twice weekly
basis for 3 to 8 weeks, whereby a cumulative dose of 280 to 290
J/cm.sup.2 is administered.
17. The method of claim 2, wherein the psoriasis is moderate to
severe psoriasis, and: a) the total daily dose of curcuminoid is
divided into 2 or 3 doses; b) the unit dose of radiation is
maintained level at 18 J/cm.sup.2, thereby providing a PASI
reduction of at least 80%; c) the device-generated radiation has an
irradiance of 2-30 mW/cm.sup.2 to achieve a radiation unit dose of
1 to 18 J/cm.sup.2 per 0.2 m.sup.2 of affected area in a subject,
wherein unit doses are administered on a 2-times per week basis,
for 3 to 8 weeks to provide a cumulative radiation dose ranging
from 150 to 200 J/cm.sup.2; and/or d) the cumulative radiation dose
administered ranges from 250-350, 250-300, 275-300 or 280-290
J/cm.sup.2.
18. The method of claim 2, wherein the psoriasis is moderate to
severe psoriasis, and the method comprises: a) orally administering
to a subject, having psoriatic plaques and a PASI ranging from
10-20, a total of 280 mg of curcuminoid on a per day basis for 3 to
8 weeks; and b) exposing psoriatic plaques of the subject to 2 to
16 J/cm.sup.2 of device-generated visible light radiation having an
irradiance of 30 mW/cm.sup.2 and at an irradiation distance of 5 cm
on a twice weekly basis for 3 to 8 weeks, thereby providing a PASI
reduction of at least 90%.
19. The method of claim 18, wherein the device-generated visible
light radiation has an irradiance of 2-30 mW/cm.sup.2 to achieve a
radiation unit dose of 17-18 J/cm.sup.2 per 0.2 m.sup.2 of affected
area in a subject, wherein unit doses are administered on a 2-times
per week basis, for 5 to 8 weeks to provide a cumulative radiation
dose ranging from 180 to 300 J/cm.sup.2.
20. The method according to claim 2, wherein the device-generated
radiation has an emission maximum at about 420 nm.
21. The method according to claim 3, wherein the device-generated
visible light radiation has an emission maximum at about 420
nm.
22. The method according to claim 13, wherein the extract is
hydroalcoholic or alcoholic extract.
23. The method according to claim 22, wherein the extract is a
hydroalcoholic extract having a Curcuminoid concentration of 12% by
wt. or an alcoholic extract having a concentration of Curcuminoid
of 90% by wt.
24. A method of psoriasis, the method comprising: a) orally
administering to a subject, having psoriasis, an effective amount
of curcuminoid, wherein the curcuminoid is curcumin; b) exposing at
least the affected area comprising psoriatic skin to
device-generated radiation comprising visible light radiation, and
optionally further comprising ultraviolet light radiation, having
an irradiance of 2 mW/cm.sup.2 or higher to achieve a unit
radiation dose of 1-36 J/cm.sup.2; and c) repeating steps a) and b)
until a PASI reduction of at least 75% is achieved in the
subject.
25. The method of claim 24, wherein the subject has a PASI of at
least 10.
26. The method of claim 24, wherein the cumulative radiation dose
is sufficient to provide a partial or full remission of the
psoriasis.
27. The method of claim 24, wherein the curcuminoid is present in
pure form or in the form of a Curcuma longa extract.
28. The method of claim 24, wherein the device-generated radiation
comprises visible light and ultraviolet light.
29. The method of claim 24, wherein the curcuminoid is administered
at a dose of 1-40 mg/kg/day.
30. The method of claim 24, wherein the exposing is conducted
1-4times per week for 2 to 10 weeks.
31. The method of claim 24, wherein the exposing is done at an
irradiation distance of 2-20 inches.
Description
TECHNICAL FIELD OF THE INVENTION
The present invention describes a method for improving the
therapeutic efficacy of formulations comprising Curcuminoids and
their analogs when they are administered systemically. The method
is characterized in that quantifiable visible and/or ultraviolet
radiation is periodically irradiated upon a patient undergoing
curcuminoid therapy for the treatment of a disease or disorder.
The present invention also describes a phototherapy device for
emitting visible light radiation over a surface greater than 0.20
m.sup.2 with an irradiance higher than 2 mW/cm.sup.2, and its use
in the treatment of dermatological and/or proliferative
diseases.
BACKGROUND OF THE INVENTION
Curcumin and its therapeutic analogs (Curcuma rhizomes, extracts,
Curcuminoids (desmethoxycurcumin, bisdesmethoxycurcumin,
tetrahydrocurcumin), prodrugs and metabolites) have been shown to
exhibit various pharmacological activities such as anti-oxidant and
antiproliferative properties, induction of apoptosis, etc. Based on
in vitro results, Curcumin offers the potential to act as a drug
for the treatment of pathologies described in the state of the art
such as psoriasis, cancer, inflammatory processes, vitiligo,
etc.
Curcumin and its equivalents reportedly exhibit very low oral
bioavailability. Br J. Cancer. 2004 Mar. 8; 90(5):1011-5 discloses
that after oral administration, only trace levels of its
metabolites were found in liver tissue, and no curcumin was found.
Therefore, an artisan would presume that Curcuminoids lack in vivo
efficacy following oral administration, and efficacy is much
reduced in vivo as compared to in vitro results. J Am Acad
Dermatol. 2008 April; 58(4):625-31 corroborates this finding
(published after priority date). The document reports that a phase
II, uncontrolled trial in patients older than 18 years who were
orally administered 4.5 g Curcuminoids/day had to be abandoned
because only 17% of patients responded to treatment with a
reduction of 75% of psoriatic plaque.
Due to the demonstrated lack of efficacy following oral
administration, an artisan of skill, such as cited in Amand et al
Biochem Pharmacol. 2008 Aug. 19. [Epub ahead of print] (published
after priority dated), would be motivated to search for solutions
for improving in vivo efficacy of Curcumin oral formulations and to
discover a "supercurcumin", if such a compound was available.
Solutions to the lack of oral efficacy that have been found
include, for example, structural modifications for improving
Curcumin absorption (EP1837030), new galenic formulations
(WO/2008/030308), and the administration of high doses in
combination of other active ingredients (U.S. Pat. No. 5,925,376,
WO03088986).
Phototherapy is a useful tool for treatment of various diseases
such as proliferative and/or dermatological pathologies (psoriasis,
cancer), acne and jaundice. Phototherapy activity is based on the
structural changes in compounds induced by the radiation.
Phototherapy is used for the treatment of jaundice in newborn. The
newborn, having a body surface area of 0.20 m.sup.2, is irradiated
with visible light, preferably with an emission maximum at 550 nm,
and an irradiance close to 40 W/m.sup.2 in order to degrade
bilirubin.
Actinic light (maximum emission at 420 nm) is used for acne
treatment based on its bactericide properties. The surface area
irradiated by these lamps is less than 400 cm.sup.2.
Photochemotherapy, concomitant administration of psoralens and
irradiation with ultraviolet light, is the treatment of choice for
moderate to severe psoriasis, but the treatment has many secondary
effects: hyperpigmentation, hepatotoxicity, hypersensitization
reactions. Sivanesan et al. (J. Am. Acad. Dermatol. (2009), 61,
793-8) discloses the results of a clinical study on the efficacy of
UVA radiation alone as compared to UVA radiation in combination
with orally administered psoralen capsules in the treatment of
psoriasis. Even after 12 weeks, the UVA radiation alone did not
reduce in any patient the PASI score by 75% in the psoriasis area.
Moreover, the irradiated dose must be carefully adjusted in order
to minimize the carcinogenic property of UV radiation.
Aminolevulinic acid combined with blue light phototherapy has been
shown to be effective in the treatment of actinic keratosis. J
Invest Dermatol. 2002 July; 119(1):77-83 describes its systemic
administration (oral) in combination with 1-20 J/cm.sup.2 visible
light (LED (light emitting diode)--maximum emission at 417 nm) for
the treatment of psoriasis, but the efficacy is limited and said
treatment cannot be used in moderate to severe psoriasis. The
results obtained showed that on 15 plaques of 1.5*1.5 cm (34
cm.sup.2) the severity of the plaques was only improved by 42%
compared to baseline.
In in vitro assays and trials employing topical administration,
photoradicals or degradants generated in situ by irradiation are
unstable and are those responsible for pharmacological activity.
Photosensitization after the administration of a photosensitizing
agent administered systemically cannot be produced immediately; the
drug must first be metabolized and, later, must be photoactivated.
In summary, effectiveness of phototherapy cannot be predicted a
priori, because it depends on bioavailability of the drug
administered and on pharmacological activity of artifacts formed
during the irradiation.
In the particular case of Curcumin, the state of the art shows that
it has very low bioavailability, and further, it is known that
Curcuminoids are degraded by visible-ultraviolet light, both in
solution and solid state. The major degradation product is a
cyclization of Curcumin by loss of 2 hydrogen atoms.
Psoriasis is a chronic disease and its etiology is not fully
understood. Clinically, psoriasis is characterized by the of
presence patches or erythematosus plaques with a dark reddish
color, delimited borders and often covered with scales that are due
to the changes in cellular proliferation marked by genetic and
immunological mechanisms. Thus, psoriasis may be considered as a
proliferative disease.
The severity of psoriasis is determined by the PASI index
(Psoriasis Area Severity Index), BSA (Body Surface Area) and PGA
(Physican Global Assessment). PASI is an objective index and is
used to evaluate drug therapeutic efficacy. According to PGA,
psoriasis may be classified into: Mild or moderate psoriasis:
lesions are under control with topical treatment; BSA<10%,
PASI<10, Moderate psoriasis: it is still possible to control the
disease with topical treatment; BSA>10%, PASI 10 or higher,
Moderate to Severe psoriasis: topical treatment cannot control the
disease; BSA>10%, PASI 10-20; very thick lesions in areas that
are difficult to treat, Severe psoriasis: systemic treatment
necessary to control the disease; BSA>20%, or PASI>20;
important local lesions of high thickness with BSA>10%.
EMEA Guidelines criteria establish that patients are considered
responders when PASI reduction is at least 75% of the baseline.
Currently, there is no widely accepted animal model to assess the
in vivo efficacy of pharmaceuticals in the treatment of psoriasis.
Drug efficacy must be tested in people who suffer from psoriasis or
in animal models by studying inhibition of tumor proliferation, for
example, the cell proliferation of the A431 cell line (cells of
epidermal carcinoma).
Efalizumab, recently authorized for psoriasis treatment, has some
efficacy. In 12 week studies, 22-35% of patients reached a score of
PASI-75 (improvement of 75%).
Photochemotherapy with Aminolevulinic acid and visible light only
showed 42% improvement in psoriatic plaques compared to baseline.
According to EMEA guidelines, the treatment lacks effectiveness, in
particular in the treatment of moderate to severe and severe
psoriasis.
Psoriasis patients tend to hide their lesions and often abandon
topical treatments, because these stain clothes. In accordance with
an opinion poll conducted by European Federation of Psoriasis
Associations, there is a high degree of dissatisfaction in
psoriasis sufferers regarding the efficacy of such treatments for
this disease and they give up treatment.
EP1133992 describes the photosensitizing activity of visible-UV
light on Curcuminoids, administered in the form of a topically
applied extract, for the treatment of psoriasis. The cream
described in EP1133992 must be applied before the radiation, but
the treatment is abandoned by patients because the Curcuma extracts
are colored and stain clothes. Moderate to severe psoriasis that
involves more than 10% of body surface area cannot be treated by
the topical route because the patients do not respond to treatments
administered via the topical route. The '992 patent discloses
irradiation of cultured human keratinocytes with UV radiation (UVA
range 340-390 nm, UVB range 290-310 nm, 150 mJ/cm.sup.2 or 1
J/cm.sup.2), and the irradiation of psoriatic skin in human
patients using visible light (weekly sessions of irradiation with a
440 nm lamp (radiation intensity unspecified) with 3 min
irradiation periods).
The results obtained in phototherapy by the topical administration
route cannot be extrapolated to systemic administration as
described for aminolevulinic acid.
Another type of phototherapy currently being used is photodynamic
therapy. The drug is administered and the patients irradiated with
a pulsed light having a high irradiance of approximately 300
mW/cm.sup.2. The light is administrated on a small surface for
short time interval, irradiating 100 J/cm.sup.2, but the method
causes pain to patients.
Exemplary phototherapy devices currently available include:
UV-Cabins emitting an irradiance of 2-30 mW/cm.sup.2 of ultraviolet
light over the whole body surface area of the patient, but without
emitting visible light, devices emitting visible light irradiating
a small surface area of approximately 500 cm.sup.2, but always less
than 10% body surface area of an adult, and Gas Discharge Lamps
having an emission range of 400-550 nm and which may be fitted to
UV-cabins, for example, Phillips TLK 40 W/03 or TLK 140 W/03 but
these lamps are used for photo printing and for aquarium
lighting.
There are also filters for selectively absorbing certain
wavelengths and transmitting radiations of 400-430 nm.
Given that to date no drug has shown efficacy in phototherapy with
visible light following oral administration of the drug, artisans
in the field would not be motivated to combine the low intensity
radiation equipment described above in order to manufacture a
phototherapy device that emits visible light having an irradiance
higher than 2 mW/cm.sup.2 over a surface greater than 0.2 m.sup.2
or greater than 40 cm.sup.2, wherein the device can be used to
treat psoriasis, cancer, tumor, vitiligo or other disorder or
disease.
SUMMARY OF THE INVENTION
An object of the invention is to improve the therapeutic efficacy
of Curcuminoids and their therapeutic equivalents when they are
administrated systemically. This improvement can be achieved by
combining systemic administration of Curcuminoids with phototherapy
employing quantifiable device-generated visible light
radiation.
Another object of the invention is to provide a method of reducing
the PASI score in a psoriatic patient. The invention provides a
treatment method whereby PASI reduction in the patient is higher
than 75%, and it is achieved in at least 80% of patients in a
population of patients in need thereof, with a probability higher
than 80% after repeated device-generated light irradiation with
radiation unit doses of 1-18 J/cm.sup.2, of either device-generated
ultraviolet light and/or device-generated visible light, thereby
meeting the efficacy criteria of the EMEA. The combined use of
systemic administration of curcuminoids and device-generated
visible light radiation and/or device-generated ultraviolet light
radiation provides additional benefits in the treatment of diseases
and disorders.
An aspect of the invention provides a method of treating a disease
or disorder having an etiology associated with excessive cell
proliferation, the method comprising: a) systemically administering
to a subject, having an affected area with a disease or disorder
having an etiology associated with excessive cell proliferation, an
effective amount of curcuminoid according to a dosing regimen; b)
exposing 0.2 m.sup.2 or greater or 40 cm.sup.2 or greater of skin
of the subject to device-generated visible light radiation having
an irradiance of 2 mW/cm.sup.2 or higher to achieve a unit
radiation dose of 1-18 or 1-36 J/cm.sup.2 per exposure; and c)
repeating steps a) and b) until a cumulative radiation dose of 150
to 560 J/cm.sup.2, or 150-600 J/cm.sup.2 during a total treatment
period is achieved.
Another aspect of the invention provides a method of treating
psoriasis, the method comprising: a) orally administering to a
subject having an affected area with psoriasis an effective amount
of curcuminoid per day; b) exposing the affected area to
device-generated visible light radiation having an irradiance of 2
mW/cm.sup.2 or higher to achieve a unit radiation dose of 1-35 or
1-36 J/cm.sup.2 per exposure or per day; and c) repeating steps a)
and b) until a cumulative radiation dose of 150 to 560 J/cm.sup.2,
or 150-600 J/cm.sup.2 during a total treatment period is achieved.
In some embodiments, a subject is exposed to radiation no more than
once per day.
The invention provides a method of improving the therapeutic
efficacy of curuminoids in the treatment of or a method of treating
a disease or disorder having an etiology associated with excessive
cell proliferation. The method comprises: a) systemically
administering to a subject, having an affected area with a disease
or disorder having an etiology associated with excessive cell
proliferation, an effective amount 25 to 2500 mg of curcuminoid per
day; b) exposing 0.2 m.sup.2 or greater or 40 cm.sup.2 or greater
of skin of the subject to device-generated visible light radiation
having an irradiance (intensity) of 2 mW/cm.sup.2 or higher for a
period of 5-100 min at an irradiation distance of 2-20 inches or
5-50 cm to achieve a radiation unit dose of 1-36 J/cm.sup.2, the
exposing being performed one to four times or two to three times
per week; and c) repeating steps a) and b) according to a dosing
regimen until a cumulative radiation dose of 150 to 560 J/cm.sup.2,
or 150-600 J/cm.sup.2 during a total treatment period is
achieved.
The invention also provides a method of treating a disease or
disorder having an etiology associated with excessive cell
proliferation, the method comprising: a) systemically administering
to a subject, having an affected area with a disease or disorder
having an etiology associated with excessive cell proliferation, an
effective amount of curcuminoid per day; b) exposing 0.2 m.sup.2 or
greater or 40 cm.sup.2 or greater of skin of the subject to
device-generated visible light radiation having an irradiance of 2
mW/cm.sup.2 or higher and a maximum wavelength in the range of 400
to 550 nm and/or of device-generated ultraviolet light having an
irradiance of 2 mW/cm.sup.2 or higher and a maximum wavelength in
the range of 315 to 400 nm for a period of 5 min or higher at a
irradiation distance of 2-20 inches, 2-10 inches, 10-20 inches or
20 inches to achieve a radiation unit dose of 1 to 18 J/cm.sup.2,
the exposing being performed on a 2 to 4 times or 2 to 3 times per
week basis; and c) repeating steps a) and b) according to a dosing
regimen until a cumulative radiation dose of 150-200 J/cm.sup.2 is
achieved during a total treatment period of two weeks or more.
The invention also provides a method of treating vitiligo in a
subject, the method comprising: a) within a total treatment period,
systemically administering to a subject, having an affected area
with vitiligo, an effective amount of curcuminoid per day; b)
within the total treatment period, exposing 0.2 m.sup.2 or greater
or 40 cm.sup.2 or greater of skin of the subject to
device-generated ultraviolet light radiation having an irradiance
of 2 to 300 mW/cm.sup.2 and a maximum wavelength in the range of
315-400 nm for a period of 5 min or higher at a irradiation
distance of 2-20 inches to achieve a radiation unit dose of 1 to 8
J/cm.sup.2, wherein said exposing is performed on a 3 to 4 times or
two times per week basis; and c) repeating steps a) and b)
according to a dosing regimen until a cumulative radiation dose of
100 to 150 J/cm.sup.2 or 120 J/cm.sup.2 is achieved during a total
treatment period of two weeks or more, whereby the affected area is
tanned and possesses acceptable pigmentation.
Some embodiments of the invention include those wherein: a) the
curcuminoid is present in pure form; b) the curcuminoid is present
as a Curcuma longa extract, e.g. a hydroalcoholic extract having a
Curcuminoid concentration of 12% by wt. or an alcoholic extract
having a concentration of Curcuminoid of 90% by wt.; c) the
systemic administration is oral or parenteral administration; d)
the curcuminoid is administered intraperitoneally; e) the
curcuminoid is administered systemically and topically; e) the
curcuminoid is any curcuminoid described or listed herein; and/or
f) the curcuminoid is not administered topically.
The terms curcumin and curcuminoid are used interchangeably herein.
In some embodiments, the therapeutic equivalents of Curcumin
(curcuminoid) are Curcuma longa extracts (hydroalcoholic extracts
having a Curcuminoids concentration of 12% or alcoholic extracts
having a concentration of Curcuminoids of 90%).
Some embodiments of the invention include those wherein the subject
is a mammal, such as a human or non-human.
Some embodiments of the invention include those wherein: a) the
disease or disorder is psoriasis, vitiligo, cancer, tumor, lichen
or lymphoma; b) the subject has a PASI index of at least 10 or
ranging from 10 to 30; c) PASI reduction in the patient is higher
than 75% at completion of the treatment period; and/or d) the
disease or disorder is moderate psoriasis, moderate to severe
psoriasis or severe psoriasis.
Some embodiments of the invention include those wherein: a) the
step of exposing comprises exposing 0.2 m.sup.2 or greater of skin
of the subject to device-generated visible light radiation having
an irradiance of 2 mW/cm.sup.2 or higher and device-generated
ultraviolet light radiation having an irradiance of 2 mW/cm.sup.2
or higher for a period of 5 min or higher effective amount of
curcuminoid is not escalated during the treatment period; c) the
period of exposing (for unit doses) is escalated during the
treatment period; d) the amount of radiation administered in a unit
dose per day ranges from 2.5 to 16 J/cm.sup.2; e) the unit dose of
radiation administered is escalated periodically by increments of 1
to 2.5 J/cm.sup.2 during the treatment period; f) the treatment
period ranges from 2 to 12 weeks, 2 to 10 weeks, 3 to 10 weeks or 3
to 8 weeks; g) the cumulative radiation dose ranges from 170-180
J/cm.sup.2; h) the unit dose of UV radiation administered is
escalated periodically by increments of 1 to 2.5 J/cm.sup.2 during
the treatment period; and/or i) the step of exposing is conducted
within 2 hours after administration of a dose of curcuminoid.
Some embodiments of the invention include those wherein: a) the
subject does not suffer hyperpigmentation as a result of the
treatment; and/or b) the method provides homogeneous pigmentation
of the affected area as a result of treatment.
Some embodiments of the invention include those wherein: a) the
visible light source has a maximum wavelength in the range from
315-550 nm or from 400-450 nm; b) the visible light source has a
maximum wavelength of about 420 nm; c) the ultraviolet light source
has a maximum wavelength in the range from 280 to 400 nm, from 280
to 315 nm (UVB) or from 315 to 400 nm (UVA); d) the ultraviolet
light source has a maximum wavelength of about 316 nm; e) the
irradiance ranges from 2 to 300 mW/cm.sup.2 or from 2 to 30
mW/cm.sup.2; and/or f) the source of device-generated light
radiation is spaced away from the affected area an irradiation
distance of 2-20 inches.
In a preferred mode, irradiance of between 2-300 mW/cm.sup.2 and
more preferably irradiances of 2-30 mW/cm.sup.2 can be used to
generate a radiation unit dose of 1-36 J/cm.sup.2 for visible light
and/or 1-18 J/cm.sup.2 for UV light.
Some embodiments of the invention include those wherein: a) the
treatment period is at least three weeks, at least one month, at
least two months or more; b) the dosing regimen for curcuminoid is
daily administration of a total daily amount of 25 to 2500 mg, 25
to 1500 mg, 25 to 1000 mg, 25 to 750 mg, 25 to 500 mg, 25 to 250
mg, 25 to 100 mg, 50 to 100 mg, 70 to 80 mg, 70 to 75 mg, 100 to
1000 mg, 200 to 1000 mg, 300 to 1000 mg, 400 to 1000 mg, 500 to
1000 mg, 600 to 1000 mg, 700 to 1000 mg, 800 to 1000 mg, about 72
mg or about 850 mg, the total amount being divided up into 1 to 5
or 1 to 3 daily doses; c) the dosing regimen for device-generated
light is 1 to 7, 2 to 6, 2 to 4 or 2 times weekly administration of
1 to 36 J/cm.sup.2 or 2 to 18 J/cm.sup.2 per administration (unit
dose of exposure); d) the total (cumulative) amount of curcuminoid
administered during the total treatment period ranges from 1400 mg
to 140 g; and/or e) the cumulative radiation dose of
device-generated light ranges from 150 to 560 J/cm.sup.2 or 150 to
600 J/cm.sup.2.
In some embodiments, Curcumin is administered parenterally
(intraperitoneally) in combination with device-generated visible
light to inhibit tumor growth in a mammal. In some embodiments,
Curcumin alone or device-generated light alone did not inhibit
tumor growth in the mammal.
The invention provides all combinations of the aspects, objects,
embodiments and sub-embodiments of the invention described
herein.
DETAILED DESCRIPTION OF THE INVENTION
The present invention seeks to overcome one or more disadvantages
of other methods in the prior art. The use of the phototherapy
system of the invention together with the systemic administration
of Curcumin or its therapeutic equivalents has higher efficacy than
the UV-cabins currently used. The oral administration of Curcumin,
Curcuminoids, their metabolites or their prodrugs with periodic
overlapping administration of unit doses of visible-ultraviolet
light radiation avoids the problems commonly associated with
photochemotherapy. By the systemic administration of curcumin or
its analogs together with irradiation, therapeutic efficacy of
curcumin is improved in vivo and efficacies higher than currently
available treatments are achieved. Moreover, the dose of
Curcuminoids administered can be, but does not have to be, adjusted
(escalated), nor is ultraviolet light radiation required when
visible light is used, even though ultraviolet light radiation can
be added into the instant methods. Unlike other radiation methods,
the radiation unit dose can be escalated during the treatment
period thereby reducing the number of phototherapy sessions and the
time required for bleaching psoriatic lesions. The present
inventors have observed that transaminases are normalized as a
result of the instant methods.
When device-generated visible light is employed without
device-generated ultraviolet light, secondary effects caused by the
ultraviolet light are avoided. This means that the administration
of corticosteroids and antihistamines for the treatment of
secondary effects caused by radiation can be avoided or minimized,
even though the invention can include embodiments wherein such
other drugs can also be administered as part of the methods herein.
The lack of adverse reactions in curcuminoid therapy and visible
light phototherapy renders possible practice of the instant patient
in pediatric, elderly and at-risk patients. Since the curcuminoids
are administered systemically, the patients' clothes are not
stained. The successful treatment of the diseases and disorders
herein provide patients with improved emotional state and personal
relations. Moreover, patients demonstrate improved compliance with
the treatment methods herein as compared to methods employing
topical administration of curcuminoids. When the combination of
device-generated visible light and device-generated ultraviolet
light are used in the instant methods, patients are uniformly
tanned without hyperpigmentation. The combined use of curcuminoid
with device-generated visible light is not hepatotoxic, and after
phototherapy, patients need not be protected from sunlight.
The combination of device-generated visible and/or ultraviolet
light with Curcuminoids gives a synergetic effect and may be used
for the treatment of all pathologies in which Curcumin might have
had potential activity. However device-generated visible light is
preferred, as the use of systemic Curcuminoids or their equivalents
enables administration of the drug with the main meals and not two
hours before radiation, meaning that the curcuminoid can be
administered at any time throughout the day and the exposure of the
subject to radiation during a 24-hour is independent of when
curcuminoid has been administered during the same 24-hour period.
The curcuminoid can be administered in the morning, afternoon,
evening or night, and the radiation can be independently
administered in the morning, afternoon, evening or night. The first
dose of radiation is generally administered to a subject after the
subject has been administered curcuminoid for a minimum of 1 to 4
days.
As used herein, the term "cumulative radiation dose" is the sum
total of all radiation unit doses to which a subject (patient) is
exposed during a total treatment period. As used herein, the term
"total treatment period" is that period of time starting with
administration of the first unit dose of curcuminoid and ending
with administration of the final unit dose of curcuminoid to a
subject. In terms of irradiation of a subject, a total treatment
period can also be that period of time starting with administration
of the first unit dose of radiation administered to a subject and
ending with administration of the final unit dose of radiation
administered to a subject.
As used herein, the term "affected area" refers to an area of skin
of a subject having a specified disease or disorder. The affected
area is comprised within the area of skin being treated by
irradiation.
As used herein, the term "device-generated light" or
"device-generated light radiation" refers to radiation generated by
a source other than the sun or moon or other natural sources of
light. Device-generated light is light generated by an electronic
and/or optical device. In some embodiments, device-generated light
excludes solar radiation.
As used herein, the term "irradiation distance" refers to the
distance between the source of device-generated light and the
surface being irradiated by the device-generated light. In some
embodiments, the irradiation distance ranges from 2 to 20 inches, 2
to 10 inches, 10 to 20 inches or 5 to 10 inches.
As used herein, the term "effective amount" is taken to mean a
pharmaceutically effective amount. A pharmaceutically effective
amount is the amount or quantity of curcuminoid which is enough for
the required or desired therapeutic response, or in other words,
the amount, which is sufficient to elicit an appreciable biological
response when, administered to a patient. The appreciable
biological response may occur as a result of administration of
single or multiple doses of an active substance. A dose may
comprise one or more dosage forms. It will be understood that the
specific dose level for any patient will depend upon a variety of
factors including the indication being treated, severity of the
indication, patient health, age, gender, weight, diet,
pharmacological response, the specific dosage form employed, and
other such factors
The invention provides a method of treating various different
diseases or disorders with curcuminoid. It also provides a method
of improving curcuminoid therapy following oral or parenteral
administration thereof. The method requires administering effective
amounts of curcuminoid to a subject in need thereof and irradiating
one or more affected areas of a subject with device-generated
visible light having a maximum wavelength in the range from 315-550
nm or from 400-450 nm and having an irradiance ranging from 2 to
300 mW/cm.sup.2 or from 2 to 30 mW/cm.sup.2. The source of visible
light radiation is spaced away from the affected area an
irradiation distance of 2 to 20 inches. The daily effective amount
of curcuminoid ranges from 25 to 2500 mg. The treatment area (that
area exposed to device-generated visible and/or device-generated
ultraviolet light radiation) will include the affected area within
it and can have a surface area of 0.2 m.sup.2 or more. The method
can further comprise a step of irradiating one or more affected
areas of a subject with device-generated ultraviolet light having a
maximum wavelength in the range from 280 to 400 nm, from 280 to 315
nm (UVB) or from 315 to 400 nm (UVA) and having an irradiance
ranging from 2 to 30 mW/cm.sup.2. The irradiation with
device-generated visible light and device-generated ultraviolet
light can be performed simultaneously, sequentially or in an
overlapping manner.
It should be understood that the unit of radiation dose, e.g.
J/cm.sup.2, refers to the amount (Joules) of radiation per cm.sup.2
of skin exposed to the radiation. The unit of irradiance, e.g.
mW/cm.sup.2, refers to the irradiance (milliWatts) per cm.sup.2 of
skin exposed to the radiation.
In another aspect, the invention provides a phototherapy system and
device for the treatment of proliferative diseases, particularly
for the treatment of moderate to severe or severe psoriasis. The
phototherapy system comprises a phototherapy device that emits
device-generated visible light over a surface area greater than 0.2
m.sup.2 and with irradiance higher than 2 mW/cm.sup.2. In a
preferred mode, the maximum wavelength is 420 nm and the light
source is LEDs, and optionally the device may have an ultraviolet
light source in order to promote a good pigmentation and a healthy
tan.
Curcuminoids, in the form of Curcumin, alcoholic Curcuma extracts
(90% Curcuminoids) or hydroalcoholic Curcuma extracts (12%
Curcuminoids), increase their therapeutic efficacy in vivo when
they are systemically administered in combination with
visible-ultraviolet light radiation (315-550 nm).
The preparation of apolar and polar extracts containing curcumin,
in particular extracts obtained by extraction of Curcuma longa
plant mass, is described in U.S. Pat. No. 6,440,468 to Quintanilla
et al., EP1133992 (equivalent to U.S. Pat. No. 6,841,177 and
PCT/ES00/00354 and related to U.S. Pat. No. 7,220,438) to
Quintanilla et al., and ES2103689, the entire disclosures of which
is hereby incorporated by reference.
Exemplary curcuminoids include curcumin (diferuloylmethane),
desmethoxycurcumin (hydroxycinnamoyl feruloylmethane), and/or
bis-desmethoxycurcumin (dihydroxydicinnamoyl methane) (see Drug
Analysis by Chromatography and Microscopy, p. 169, Ann Arbor
Science Inc., 1973), which may be purchased from commercial sources
or isolated from turmeric. Methods for isolating curcuminoids from
turmeric are known, (see Janaki and Bose, An Improved Method for
the Isolation of Curcumin From Turmeric, J. Indian Chem. Soc. 44:
985 (1967)). Alternatively, curcuminoids for use in the present
invention can be prepared by synthetic methods. Curcumin not only
has antioxidant properties but also may have anti-inflammatory,
anti-tumor and other valuable properties.
Alternatively, other therapeutic equivalents or analogs of
Curcuminoids can be used, for example those described by Anand et
al (Biochem Pharmacol. (2008) Aug. 19. [Epub ahead of print]),
curcuma rhizomes or Curcumin cyclised by the action of irradiation
increase their in vivo efficacy when concomitantly administered
with visible-ultraviolet radiation.
The combination treatment of oral administration of Curcuminoids
and irradiation with visible light Curcuminoids exhibits the same
efficacy in moderate to severe psoriasis as the combination of oral
administration of Curcuminoids and irradiation with ultraviolet
light.
Example I describes a clinical trial conducted to evaluate the
efficacy of the method of the invention in the treatment of
moderate to severe psoriasis with device-generated ultraviolet
light over a total treatment period of 8 weeks. The initially PASI
of subjects, group according to phototype I, II, III or IV, was
determined. Subjects were then administered tablets containing 24
mg curcuminoid three times daily (each tablet taken before a main
meal) for a total daily dose of 72 mg. Subjects were treated with
UV radiation (UVA, 315-400 nm, 365 nm wavelength maximum) twice
weekly for a total of 16 radiation treatments. The initial
radiation unit dose was initially 2.5 J/cm.sup.2, which was
escalated by 0.5-1 J/cm.sup.2 and then by 2 J/cm.sup.2 until
reaching a per day unit dose of 16 J/cm.sup.2, which dose took
about 30 min to administer. After each radiation treatment, the
PASI of each subject was determined again. The cumulative radiation
dose ranged from 170 to 180 J/cm.sup.2 during the total treatment
period of 8 weeks. All patients achieved the target 16 J/cm.sup.2
dose and hyperpigmentation resulting from radiation was not
observed. By the end of 8 weeks, all patients achieved a PASI
reduction of at least 80%.
Accordingly, the invention provides a method of treating moderate
to severe psoriasis comprising: systemically (orally) administering
to a subject, having a PASI ranging from 10-20, a total of 70 to 80
mg of curcuminoid on a per day basis for a total treatment period
of 3 to 8 weeks; and exposing at least 0.2 m.sup.2 of skin
(comprising a psoriatic area) of the subject 2.5 to 16 J/cm.sup.2
unit doses of device-generated ultraviolet light on a twice weekly
basis for a total treatment period of 3 to 8 weeks, thereby
providing a PASI reduction of at least 80%. In some embodiments,
the total daily dose of curcuminoid is divided into 2 or 3 doses.
In some embodiments, the unit dose of radiation is escalated from
2.5 to 16 J/cm.sup.2 during the treatment period in escalation
increments of 0.5 to 1 J/cm.sup.2. In some embodiments, the unit
dose of radiation is maintained level after reaching a target
maximum, e.g. after reaching 16 to 18 J/cm.sup.2. In some
embodiments, the cumulative radiation dose during the total
treatment period ranges from 150 to 250, 150-200 or 170-180
J/cm.sup.2.
Example II describes a clinical trail conducted to evaluate the
efficacy of the method of the invention in the treatment of
moderate to severe psoriasis with visible light over a total
treatment period of 8 weeks. The initially PASI of subjects, group
according to phototype I, II, III or IV, was determined. Subjects
were then administered tablets containing 24 mg curcuminoid three
times daily (each tablet taken before a main meal) for a total
daily dose of 72 mg. The entire bodies (about 2.4 m.sup.2) of naked
subjects were treated with visible light (400-550 nm, 420 nm
wavelength maximum) twice weekly for a total of 16 radiation
treatments. The radiation unit dose was maintained at 18
J/cm.sup.2, which dose took about 1 hour and 40 min to administer.
After each radiation treatment, the PASI of each subject was
determined again. By the end of 8 weeks, all patients achieved a
PASI reduction of at least 80%.
Accordingly, the invention provides a method of treating moderate
to severe psoriasis comprising: systemically (orally) administering
to a subject, having a PASI ranging from 10-20, a total of 70 to 80
mg of curcuminoid on a per day basis for a total treatment period
of 3 to 8 weeks; and exposing the entire naked body of a psoriatic
subject to a unit dose of about 18 J/cm.sup.2 of visible light on a
twice weekly basis for a total treatment period of 3 to 8 weeks,
whereby a cumulative radiation dose of 280 to 290 J/cm.sup.2 is
administered to each patient. In some embodiments, the total daily
dose of curcuminoid is divided into 2 or 3 doses. In some
embodiments, the dose of radiation is maintained level at 18
J/cm.sup.2, thereby providing a PASI reduction of at least 80%. In
some embodiments, the cumulative radiation dose administered during
the total treatment period ranges from 250-350, 250-300, 275-300 or
280-290 J/cm.sup.2.
Example III describes a clinical trial somewhat similar to that of
Example II, except that only 40 cm.sup.2 of treatment area
(including the 30-35 cm.sup.2 of affected area of the back or
gluteus of a patient) was exposed to device-generated visible light
radiation. Moveover, an irradiation distance of 5 cm and an
irradiance of 30 mW/cm.sup.2 were used. Also, patients were
administered one capsule per day containing 280 mg of curcuminoids.
The irradiation doses were escalated from 2 J/cm.sup.2 to 16
J/cm.sup.2, thereby providing a PASI reduction of at least 90% in
each patient over a total treatment period of 8 weeks.
Accordingly, the invention provides a method of treating moderate
to severe psoriasis comprising: systemically (orally) administering
to a subject, having a PASI ranging from 10-20, a total of 280 mg
of curcuminoid on a per day basis for a total treatment period of 3
to 8 weeks; and exposing 40 cm.sup.2 (or 30-35 cm.sup.2) of
treatment area of a psoriatic subject to 2 to 16 J/cm.sup.2 of
device-generated visible light having an irradiance of 30
mW/cm.sup.2 and at an irradiation distance of 5 cm on a twice
weekly basis for a total treatment period of 3 to 8 weeks, thereby
providing a PASI reduction of at least 90%.
Example IV describes a clinical trail conducted to evaluate the
efficacy of the method of the invention in the treatment of
vitiligo with ultraviolet light over a total treatment period of 8
weeks. Subjects were then administered tablets containing 24 mg
curcuminoid three times daily for a total daily dose of 72 mg. The
affected areas of subjects were treated with ultraviolet light
(315-400 nm, 365 nm wavelength maximum) twice weekly for a total of
16 radiation treatments. The radiation dose was escalated from an
initial dose of 1 J/cm.sup.2 to a maintenance dose of 8 J/cm.sup.2
using dose escalation increments of 2 J/cm.sup.2 until reaching a
dose of 7 J/cm.sup.2 and then using a dose escalation of 1
J/cm.sup.2. By the end of 8 weeks, all patients achieved a
significant improvement and enjoyed good homogeneous tanning
without hyperpigmentation or burning. The combination of
Curcuminoids/ultraviolet light produced pigmentation in the
patients treated without causing burns. The combination of
Curcuminoids/visible light plus ultraviolet light will allow
homogenous pigmentation of all patients who are treated with
Curcuminoids/visible light.
Accordingly, the invention provides a method of treating vitiligo
comprising: systemically (orally) administering to a subject a
total of 70-80 mg or about 72 mg of curcuminoid on a per day basis
for a total treatment period of 8 weeks; and exposing the vitiligo
affected area of a subject to 1 to 8 J/cm.sup.2 of ultraviolet
light on a twice weekly basis for a total treatment period of 8
weeks, thereby providing homogeneous or good tanning without
hyperpigmentation of the affected area. In some embodiments, the
dose of radiation is escalated from 1 to 8 J/cm.sup.2 during the
treatment period in escalation increments of 1 to 2 J/cm.sup.2.
Example V describes a mouse model used to evaluate the efficacy of
the method of the invention in the treatment of cancer. Visible
light was irradiated on mice and combined with intraperitoneal
administration of curcumin to produce a 70% inhibition of the
proliferation of human epidermal carcinoma cells (A431). In
contrast to J. Am. Acad. Dermatol. 2008 April; 58(4):625-31, which
reported that Curcuminoids administered at doses of 4.5 g/day
lacked efficacy in the treatment of psoriasis, the present
inventors have discovered that the combination of Curcuminoids with
quantifiable device generated light, either ultraviolet or visible,
is effective in treating psoriasis. All patients achieved a PASI
reduction of 75% or higher, and no patient abandoned the therapy.
In the middle of the trial described herein, in week four (after 8
phototherapy sessions), 50% of patients reached a PASI reduction
greater than 75% of baseline. In the middle of trial described
herein, the efficacy (therapeutic response) was higher than the
therapy with Efalizumab after 12 weeks of treatment and was without
secondary (adverse) effects.
Accordingly, the invention provides a method of improving
curcuminoid therapy by combining systemic administration of a low
amount of curcuminoid with a high amount of visible light
radiation. That the inventors were able to demonstrate efficacy
with reduced systemic doses of curcumoid in the presence of visible
or ultraviolet light is especially surprising, since curcumin is
degraded in the presence of light in solution and in solid
state.
The combination of visible light and systematically administered
Curcuminoids is expected to be effective for the treatment of any
tumor type, for example, epidermal, esophageal, duodenum, colon,
breast, liver, kidney or prostate. In some embodiments, the cancer
or tumor is skin cancer.
In the case of using device-generated visible light, any irradiance
and any type of light can be used, for example incoherent,
polarized, pulsed or laser due to the absence of secondary effects.
The light should have an irradiance ranging from 2 mW/cm.sup.2 to
300 mW/cm.sup.2 or 2 mW/cm.sup.2 to 30 mW/cm.sup.2
The curcuminoid and device-generated light are administered to a
subject in need thereof according to a specified dosing regimen,
which may be the same or can change throughout a treatment period.
The curcuminoid can be administered according to a dosing regimen
that is the same as or different than the dosing regimen for the
device-generated light. Each dosing regimen can comprise once,
twice, three, four-times or more per day administration. The per
day administration can be repeated in a week one to seven times
weekly, every day, every other day, two times per week, three times
per week, four times per week, five times per week. The number of
weeks per month that the per day administration can be administered
can be 1 to 5 weeks per month, weekly, or every other week. The
number of months per year that the per day administration can be
administered can be 1 to 12 months, monthly, bimonthly, quarterly,
trimesterly or biannually. Accordingly, the treatment period for
the method of the invention can range from 1 week to 1 year, 1 week
to 6 months, 1 week to 8 weeks. The treatment period will end when
the desired clinical benefit has been achieved in a subject. If the
subject is being treated for psoriasis, the treatment period can
end at or after the time point when the subject has experienced at
least a 75% reduction or at least an 80% reduction in the PASI
score. If the subject is being treated for cancer or tumor, the
treatment period can end at or after the time point when the
subject has experienced a slowing or reversal of progression or a
partial or complete remission.
In some embodiments, curcuminoid is administered according to the
following dosing regimen: a) 20-2500 mg per day for a treatment
period of 1 to 52 weeks; b) 280-600 mg per day for 8 weeks; or c)
other dosing regimen, which may be defined by a clinician and the
specific needs, diagnosis, or prognosis of a subject being
treated.
In some embodiments, the device-generated light is administered
according to the following dosing regimen: a) device-generated
light having an irradiance of 2-300 mW/cm.sup.2 to achieve a
radiation unit dose of 1 to 36 J/cm.sup.2 or 1 to 18 J/cm.sup.2 per
0.2 m.sup.2 of affected area (or of skin treated) in a subject,
wherein unit doses are administered on a 1 to 4 times per week
basis, for a treatment period of 2 to 10 weeks to provide a
cumulative radiation dose ranging from 150 to 580 J/cm.sup.2 or 150
to 600 J/cm.sup.2; b) device-generated visible light having an
irradiance of 2-30 mW/cm.sup.2 to achieve a radiation unit dose of
1 to 18 J/cm.sup.2 per 0.2 m.sup.2 of affected area (or of skin
treated) in a subject, wherein unit doses are administered on a
2-times per week basis, for a treatment period of 3 to 8 weeks to
provide a cumulative radiation dose ranging from 150 to 200
J/cm.sup.2; or c) device-generated visible light having an
irradiance of 2-30 mW/cm.sup.2 to achieve a radiation unit dose of
17-18 J/cm.sup.2 per 0.2 m.sup.2 of affected area (or of skin
treated) in a subject, wherein unit doses are administered on a
2-times per week basis, for a treatment period of 5 to 8 weeks to
provide a cumulative radiation dose ranging from 180 to 300
J/cm.sup.2. The radiation unit dose can be escalated by increments
of 0.1 to 2 J/cm.sup.2, 0.5 to 2 J/cm.sup.2, 1 to 2 J/cm.sup.2, 1.5
to 2 J/cm.sup.2 for UV radiation and 2 to 8 J/cm.sup.2 or 2 to 16
J/cm.sup.2 or 2 to 32 J/cm.sup.2 for visible light.
The combination of Curcuminoids/visible-ultraviolet light is
effective therapeutically at doses lower than those described in
the state of the art, for example 1-10 mg/kg/day in psoriasis by
oral administration or 10-50 mg/kg/day in the inhibition of tumors
in a mouse model by intraperitoneal administration.
Thus, formulations comprising at least a Curcuminoid or analog
together with excipients acceptable for systemic administration,
and optionally other active principles, can be developed. The
formulation used in the method is adapted for systemic
administration of curcuminoid. Exemplary types of formulations
include oral, buccal, parenteral, otic, ophthalmic, nasal,
inhalable, sublingual, enteral, oral, peroral, and injectable
dosage forms. Particular dosage forms include a solid, suspension,
gel or liquid dosage forms. Exemplary suitable dosage forms include
tablet, capsule, pill, caplet, troche, sache, solution, suspension,
dispersion, vial, ampoule, bag, bottle, syringe, injectable liquid,
i.v. (intravenous), i.m. (intramuscular) or i.p. (intraperitoneal)
administrable liquid and other such dosage forms known to the
artisan of ordinary skill in the pharmaceutical sciences. A dosage
form can be packaged using conventional packaging equipment and
materials. It can be included in a pack, envelope, packet, blister
pack, box or other such container.
A dosage form can be made by any conventional means known in the
pharmaceutical industry. A liquid dosage form can be prepared by
providing at least one liquid carrier and curcuminoid or
curcuminoid-containing extract in a container. One or more other
excipients can be included in the liquid dosage form. A solid
dosage form can be prepared by providing at least one solid carrier
and curcuminoid or curcuminoid-containing extract. One or more
other excipients can be included in the solid dosage form.
A liquid, suspension or gel formulation can comprise one or more
pharmaceutically acceptable liquid carriers. The liquid carrier can
be an aqueous, non-aqueous, polar, non-polar, and/or organic
carrier. Liquid carriers include, by way of example and without
limitation, a water miscible solvent, water immiscible solvent,
water, buffer and mixtures thereof.
Although not necessary, a formulation or kit of the present
invention may include a chelating agent, preservative, antioxidant,
adsorbents, acidifying agent, alkalizing agent, antifoaming agent,
binding, buffering agent, colorant, diluent, electrolyte, filler,
preservative, salt, stabilizer, surfactant, tonicity modifier,
other pharmaceutical excipient, or a combination thereof.
A subject treated according to the invention will exhibit a
therapeutic response. By "therapeutic response" is meant that a
subject suffering from the disease or disorder will enjoy at least
one of the following clinical benefits as a result of treatment
with systemically administered curcuminoid and phototherapy:
amelioration of the disease or disorder, reduction in the
occurrence of symptoms associated with the disease or disorder,
partial remission of the disease or disorder, full remission of the
disease or disorder, or increased time to progression. In other
words, the therapeutic response can be a full or partial
therapeutic response.
Once a drug has been discovered that is capable of increasing its
efficacy when administered concomitantly with visible light, an
expert in the field can develop any phototherapy system comprising
the means to emit a visible wavelength (400-550 nm) with an
irradiance greater than 2 mW/cm.sup.2 on a surface greater than
0.20 m.sup.2. Light sources that can be used according to the
invention include, for example, gas discharge lamps, LEDs,
polarized light, a laser beam or filtered solar radiation.
Among gas discharge lamps emitting in the range of 400-550 nm with
a maximum at 420 nm are the Phillips TLK 40 W/03 and Phillips TLK
140 W/03. Their dimensions are 60*4 cm and 140*4 cm respectively.
Ten Phillips TLK 40 W/03 lamps at a distance of 45 cm emit 5500
l.times., that is a irradiance of 2 mW/cm.sup.2. Logically, if the
distance between the source and the radiation surface is reduced,
the irradiance would increase. A source having an irradiance of 2
mW/cm.sup.2 emitting for 20 minutes will give a dose of
3*20*60/1000 J/cm.sup.2=3.6 J/cm.sup.2. Such lamps can be connected
without difficulty to the current phototherapy cabins that use
ultraviolet light discharge tubes.
The development of LED technology allows obtaining radiations with
a greater luminous efficiency and with a very narrow wavelength
emission (.+-.5 nm) and can used in phototherapy. J Invest
Dermatol. 2002 July; 119(1):77-83 discloses LED panels that radiate
over a surface of 30 cm.sup.2 with an irradiance of 9-11
mW/cm.sup.2, but the distance between the source and the psoriatic
plaque was not specified. If the distance between the source and
surface irradiated is reduced then irradiance will be greater but
irradiation surface area will be smaller. Irradiating at a distance
of 5 cm, it is possible to achieve irradiances of 30 mW/cm.sup.2
with currently commercially available LEDs.
In the same way, increasing the number of panels of LEDs increases
the radiated surface. 60 panels of 12*25 cm, similar to those
described in J Invest Dermatol. 2002 July; 119(1):77-83, would
irradiate over the whole adult body surface with an irradiance of
30 mW/cm.sup.2 at a distance of 5 cm in order to treat the moderate
to severe psoriasis.
It should be noted that small spectral variations in radiation or
incidence angles will modify the radiometric measurements. For
example, radiant energy depends on wavelength of the radiation
according to E=h.upsilon. wherein h is Planck's contant and
.upsilon. is frequency of wavelength, but irradiation sources are
not monochromatic and radiometric measurements may vary depending
frequency distribution in the irradiation sources.
In view of the above description and the examples below, one of
ordinary skill in the art will be able to practice the invention as
claimed without undue experimentation. The foregoing will be better
understood with reference to the following examples that detail
certain procedures for the preparation of embodiments of the
present invention. All references made to these examples are for
the purposes of illustration. The following examples should not be
considered exhaustive, but merely illustrative of only a few of the
many embodiments contemplated by the present invention.
EXAMPLE I
Effect of an Orally Administered Hydroalcoholic Extract of Curcuma
longa in Combination with Ultraviolet Light in Moderate to Severe
Psoriasis
A pilot clinical trial was designed for the treatment of patients
diagnosed with chronic psoriasis with moderate to severe plaques in
which other treatments such as cyclosporine, psoralenes/UVA or
corticoids had previously failed. The study parameters were as
follows. number of patients: 22. trial duration: 8 weeks//16
ultraviolet radiation sessions, or two UV radiation sessions per
week. Medication: 24 mg of Curcuminoids per tablet, in the form of
hydroalcoholic Curcuma longa extract having a Curcuminoids
concentration of 12%. The excipients used in the formulation were:
cellulose, magnesium stearate, corn starch, sodium starch
glycolate, potassium hydrogen phosphate and silicon dioxide. The pH
of one tablet dispersed in water (5% w/v) was 5. Administration
regime: 3 tablets/day before main meals (72 mg Curcuminoids/day);
Radiation source: PUVA COMBI LIGHT cabin with 32 lamps of Philips
UVA 100 W (315-400 nm, maximum 365 nm). Irradiated surface: all the
naked body surface except genitals of the subjects, approximately 2
m.sup.2. Irradiation distance: about 45 cm (the radiation cabin was
approximately 80.times.80 cm.sup.2 and the patient was placed in
the middle of the cabin. Doses: 2 phototherapy sessions per week
were administered. The initial dose was 2.5 J/cm.sup.2. The dose
was increased by 0.5-1 J/cm.sup.2 until reaching a slight erythema
and later increased by 2 J/cm.sup.2 per session until reaching 16
J/cm.sup.2. The radiation time to reach 16 J/cm.sup.2 was
approximately 30 minutes.
Rescue medication was used as needed: a topical emollient
formulation containing vitamin B3 for the symptomatic relief of
cutaneous manifestations; oral desloratadine (5 mg), if itching
occurred.
The Curcuma extract was obtained according the following process:
extraction of rhizomes of Curcuma longa with ethanol, evaporation
of the solvent and quantification of the Curcuminoids content
expressed as Curcumin; extraction of the rhizomes of the previous
phase with water and evaporation of the solvent; the resultant
extracts were mixed and an extract was obtained with a Curcuminoids
concentration of 10-15%.
The phototypes of the patients were I, II, III, IV. The average
weight was 70 kg. The determination of skin phototype was performed
according to the Fitzpatrick Classification Scale.
PASI reduction is detailed in following table for the different
visits V1-V16 (2 visits per week). The patients who achieved a PASI
reduction of more than 90% left the study.
TABLE-US-00001 PASI Reduction Patient Visit No 1 2 3 4 5 6 7 8 9 10
11 12 13 14 15 16 17 18 19 20 21 22 v1 11 36 42 0 15 24 35 25 0 7
20 13 11 17 32 40 34 48 31 53 49 49 V2 31 51 63 21 43 65 53 35 6 45
17 25 32 21 47 60 61 52 49 54 58 69 v3 25 36 54 35 35 54 55 54 21
39 39 38 44 54 55 78 82 82 61 60 73 65 V4 47 41 63 33 44 69 55 26
30 36 36 47 59 45 40 80 83 84 63 75 79 67 V5 49 50 59 26 47 73 63
42 36 45 51 39 68 66 53 86 85 87 78 75 82 79 V6 26 56 52 40 47 78
70 42 38 37 72 54 73 73 52 82 89 96 80 78 85 85 V7 37 67 47 35 69
78 73 52 40 54 79 63 69 73 62 88 93 84 79 87 85 V8 45 67 59 69 69
78 80 67 48 42 77 37 69 77 62 89 85 85 92 88 V9 57 67 64 67 73 92
80 67 46 50 76 63 69 79 70 89 91 87 93 V10 76 73 71 68 66 93 83 44
67 78 67 82 82 70 90 88 V11 80 77 74 80 69 81 47 57 86 69 82 85 76
91 90 V12 79 77 77 74 80 80 59 69 82 82 89 84 80 V13 79 81 84 77 87
80 70 70 82 86 91 87 80 V14 79 87 82 75 89 83 70 66 89 87 86 81 V15
81 81 82 77 89 87 75 78 86 85 88 82 V16 91 89 87 88 93 93 76 86 94
87 88 82
For example, the doses irradiated to patients, 1, 2, 3 and 9
were:
TABLE-US-00002 Patient 1 2 3 9 Phototype III II I IV VISIT 1 2.5
2.5 2.5 2.5 VISIT 2 3.5 3.5 3.5 3.5 VISIT 3 4.5 4.5 4.5 4 VISIT 4
5.5 5.5 5.5 5 VISIT 5 5.5 7.5 6.5 6 VISIT 6 7.5 9.5 8.5 8 VISIT 7
9.5 11.5 10.5 10 VISIT 8 11.5 13.5 12.5 12 VISIT 9 13.5 15.5 14.5
14 VISIT 10 15.5 16 15.5 15 VISIT 11 16 16 16 15.5 VISIT 12 16 16
16 16 VISIT 13 16 16 16 16 VISIT 14 16 16 16 16 VISIT 15 16 16 16
16 VISIT 16 16 16 16 16
The 22 patients reached the radiation of 16 J/cm.sup.2 and the
accumulated dose were of the order of 170-180 J/cm.sup.2.
No patient abandoned the treatment and radiation was well tolerated
without severe photo toxicity reactions. Only one patient received
a 5 mg desloratadine tablet.
After the 7th phototherapy session, the patients showed a healthy
tan without stains or hyperpigmentations. Hyperpigmentations did
not appear in any patient.
Hepatic parameters were within the normal range and hepatotoxicity
was not identified. An increase of the red series was observed.
At the end of trial, the patients was pleased with the therapy and
the commented that their self-esteem and personal relations had
improved.
The results show the potential use of Curcumin, Curcuminoids,
metabolites or their prodrugs as sun filters against
visible-ultraviolet radiation. That is, hyperpigmentations were not
produced in patients with phototypes III and IV and erythema and
freckles were avoided in patients with fair skin.
In the middle of the trial, after fourth weeks and only 8
phototherapy sessions, 50% of patients reached PASI reductions
higher than 75%. The efficacy in the middle of trial, was similar
to that of Efalizumab in 12 weeks and without secondary
effects.
All the patients reached a PASI reduction of at least 80%.
EXAMPLE II
Effect of Orally Administered Hydroalcoholic Extract of Curcuma
longa in Combination with Visible Light in Moderate to Severe
Psoriasis
The parameters of this study were as follows. Number of patients:
10 Duration of trial: 8-weeks//16 phototherapy sessions with
visible light. Medication: 24 mg tablets of Curcuminoids in the
form of a hydroalcoholic Curcuma longa extract with a Curcuminoids
concentration of 12%. The excipients used in the formulation were:
cellulose, magnesium stearate, corn starch, sodium starch
glycolate, potassium hydrogen phosphate and silicon dioxide. The pH
of 1 tablet dispersed in water (5% w/v) was 5. The Curcuma extract
was obtained as in the above trial. Administration regime: 3
tablets/day before meals (total of 72 mg Curcuminoids/day)
Radiation source: Phillips TLK 40 W/03 lamp giving 5500 l.times.
visible light 100*40 W, 400-550 nm maximum emission 420 nm.
Irradiated surface: 100*60*4 cm=2.4 m.sup.2 over the naked body
surface. Irradiation distance: about 45 cm Irradiation doses: 2
phototherapy sessions per week. The irradiated doses were 18
J/cm.sup.2, irradiation time: 1 hour 40 minutes.
Rescue medication was used as needed: a topical emollient
formulation containing vitamin B3 for the symptomatic relief of
cutaneous manifestations; oral desloratadine (5 mg), if itching
occurred.
The phototypes of the patients studied were skin types II and III.
The average weight was 70 kg.
PASI reduction is detailed in following table for the different
visits V1-V16 (2 visits per week). The patients who achieved a PASI
reduction higher than 90% left the study.
TABLE-US-00003 PASI reduction Patient VISIT 1 2 3 4 5 6 7 8 9 10 V1
23 17 48 30 40 42 37 25 0 30 V2 25 40 54 42 35 50 49 54 12 42 V3 31
38 63 61 44 57 65 46 25 57 V4 39 50 77 62 47 69 69 66 26 66 V5 47
70 80 70 47 75 81 72 39 73 V6 56 78 83 68 69 79 83 72 45 67 V7 45
78 85 69 69 78 86 77 48 67 V8 68 79 89 70 75 88 87 79 59 78 V9 65
86 92 78 79 93 91 83 65 83 V10 70 82 80 85 85 73 85 V11 79 85 84 85
80 76 86 V12 79 84 87 91 84 80 95 V13 79 87 85 87 84 V14 82 81 86
88 84 V15 85 89 88 88 86 V16 85 90 89 88 87
The results obtained show the same efficacy was achieved with
visible light as with ultraviolet light (Example I). All the
patients exhibited a PASI reduction of more than 80% before 8 weeks
of treatment.
The treatment was well tolerated and antihistamines and corticoids
were not administered.
EXAMPLE III
Effect of Orally Administered Alcoholic Extract of Curcuma longa in
Combination with Visible Light in Moderate to Severe Psoriasis
A clinical trial was conducted on 4 patients with average age of 48
years, average weight of 68 kg, diagnosed with moderate to severe
psoriasis.
The diagnostic criteria were the PASI on psoriatic plaque on the
back or gluteus with a surface area of 30-35 cm.sup.2.
The irradiation was carried out with a LED lamp, maximum emission
420 nm (visible light). The irradiation distance was 5 cm with an
irradiance of 30 mW/cm.sup.2 over a surface of 40 cm.sup.2.
After the screening visit to carry out the electrocardiogram and
analytical determinations on included patients, the most important
plaque with a surface area of between 30-35 cm.sup.2 was chosen for
each patient.
The patients received one capsule/day containing 280 mg of
Curcuminoids, as an alcoholic extract with 90% in Curcuminoids. The
selected plaque was irradiated a week after the start of Curcuma
extract treatment and irradiations continued with two phototherapy
sessions per week. The initial radiation dose was 2 J/cm2 and was
progressively increased to 16 J/cm.sup.2.
The four patients reached a PASI reduction of more than 90% of
baseline after 8 weeks on the irradiated plaque.
EXAMPLE IV
Effect of Orally Administered Hydroalcoholic Extract of Curcuma
longa in Combination with Ultraviolet Light in Vitiligo
Six patients diagnosed with vitiligo were treated with 3
tablets/day of an hydroalcoholic extract of Curcuma (72 mg
Curcuminoids/day) and irradiation in a UV-cabin (315-400 nm,
maximum 365 nm). The initial dose was 1 J/cm.sup.2 and was
increased (escalated) by 2 J/cm.sup.2 up to 7 J/cm.sup.2. The last
irradiation sessions were at 8 J/cm.sup.2. A summary of the
patients' initial symptomology, treatment and outcome observed
follows.
TABLE-US-00004 Patient Presenting Treatment Outcome 1 Generalized
vitiligo 8 phototherapy A quick tan was achieved with a large
facial sessions. without burns or erythema patch. 2 Vitiligo with
patches on 8 phototherapy Pigmentation foci appeared on hands, chin
and legs. sessions of 12 the edges of some vitiligo J/cm.sup.2 on
the hands. patches. 3 Extensive vitiligo 8 phototherapy Good
tanning. The re- associated with sessions. pigmentation process was
fibromyalgia and observed on the neck. thyroid disorder 4 Extensive
vitiligo. 8 phototherapy Rapid increase in tan without
Hypothyroidism. sessions. burns. Pigmentation appeared on the
abdomen. 5 Extensive vitiligo with 8 phototherapy Good tanning
without burning. large facial patches sessions. Appearance of
pigmentation of face and neck. 6 Extensive vitiligo with 8
phototherapy Good tanning. Vitiligo on the large facial patches.
sessions. joints. Presence of pigmentation on the elbows.
EXAMPLE V
Effect of Curcumin by Intraperitoneal Administration on Inhibition
of Tumor Growth in Mice in Combination with Visible Light
5*10.sup.6 A431 cells (human epidermal carcinoma) were injected
subcutaneously into the left and right flanks of athymic nude mice
(NMRI) (5-6 weeks old, 20-24 g). The mice were fed in pathogen-free
conditions. The animals were fed ad libitum with sterilized food.
The animals were sterilized with ketamine/xylazine. For the
treatment, 5 mg Curcumin were dissolved first in 50 .mu.l of
ethanol and further diluted in 2 ml of 1% methylcellulose and
sterilised. The mice were fed intraperitoneally twice a day with
200 .mu.l of the solution or methylcellulose solution alone at a
dose of 50 mg Curcuminoids/kg per day.
After intraperitoneal injection, one group of mice (Curcumin and
methylcellulose) was irradiated for 20 minutes with 5500 l.times..
The irradiation device was 10 Phillips TLK 40 W/03 lamps (60 cm
length*4 cm diameter), at a distance of 45 cm. The emission range
of the lamps was between 400-550 nm with a maximum at 420 nm.
Three groups (the control group, methylcellulose group and Curcumin
without irradiation group) were protected from light for 1 hour
after infection. Tumor size was measured initially and after 10-12
days; afterwards tumor volumes and weights were determined twice a
week. At the end of the experiment (29 days), the animals were
anesthetized and sacrificed.
The results demonstrate that only the group treated with Curcumin
and visible light showed a significant difference in inhibition of
tumor growth compared with the control group. The average tumor
volume at day 12 in Curcumin/light treated mice was reduced by 70%
in comparison to control mice. The tumor volume of the
Curcumin-treated but not irradiated group was not significantly
reduced (p=0.16), that is visible light improved the efficacy of
Curcuminoids in vivo.
As used herein, the term "about" or "approximately" is taken to
mean .+-.10%, .+-.5%, .+-.2.5% or .+-.1% of a specified value.
The above is a detailed description of particular embodiments of
the invention. It will be appreciated that, although specific
embodiments of the invention have been described herein for
purposes of illustration, various modifications may be made without
departing from the spirit and scope of the invention. Accordingly,
the invention is not limited except as by the appended claims. All
of the embodiments disclosed and claimed herein can be made and
executed without undue experimentation in light of the present
disclosure.
* * * * *